The invention relates to derivatives of azetidine and pyrrolidine, to pharmaceutical compositions comprising the same, a process for their preparation, as well as the use of derivatives of azetidine and pyrrolidine for the preparation of a medicament which acts on the central nervous system.
In recent years the contribution of serotonergic activity to the mode of action of antidepressant drugs has been well documented and compounds which enhance activity in the serotonin system have been developed and successfully introduced as antidepressants. Serotonin reuptake inhibitors (SRI) work by increasing the amount of serotonin available at the synapse. Although the SRI""s have more favourable side effect profiles than previous generations, they are not devoid of side effects and still suffer from a slow onset of action [Andrews and Nemeroff, xe2x80x9cContemporary management of depressionxe2x80x9dxe2x80x94American Journal of Medicine 97(6A): 24S-32S (1994); Leonard, xe2x80x9cThe comparative pharmacology of new antidepressantsxe2x80x9dxe2x80x94Journal of Clinical Psychiatry 54(Suppl): 3-15 (1993)]. Moreover, the mechanism of action of the SRI""s although specific for serotonin, is not selective in that they effect activity at a multitude of different serotonin receptor subtypes. This broad spectrum of activity may lead to many of the side effects associated with the SRI""s e.g. nausea from activation of 5-HT3, headache due to activation of 5-HT2B. Thus, SRI""s can alter the function of several 5-HT2 receptor subtypes, however, the efficacy of these drugs may correlate most strongly with their effects on the 5-HT2C system [(Broekkamp and Berendsen xe2x80x9cThe importance of 5-HT1C receptors for anti-depressant effectsxe2x80x9dxe2x80x94Polish Journal of Pharmacology and Pharmacy 44(Suppl): 20 (1992); Cesana et at xe2x80x9cMesulergine antagonism towards the fluoxetine anti-immobility effect in the forced swimming test in micexe2x80x9dxe2x80x94Journal of Pharmacy and Pharmacology 45: 473-475 (1993); Berendsen and Broekkamp xe2x80x9cComparison of stimulus properties of fluoxetine and 5-HT receptor agonists in a conditioned taste aversion procedurexe2x80x9dxe2x80x94European Journal of Pharmacology 253: 83-89 (1994)]. These data suggest that compounds which selectively activate the 5-HT2C receptor will be effective in the treatment of affective disorders and related conditions.
The invention relates to compounds according to the formula I 
wherein A is an optionally unsaturated 5- or 6-membered ring, which may comprise a heteroatom selected from N, O and S and which may be substituted with oxo or (1-6C) alkyl; R1, R2 and R3 are independently H. (1-6C) alkyl, (1-6C) alkoxy, (1-6C) alkoxy-(1-6C) alkyl, carbo(1-6C) alkoxy or halogen; X is O or S; and n is 1 or 2; or a pharmaceutically acceptable salt thereof, with the exception of 3-(naphth-1-yl-oxy)-pyrrolidin and 3-(5,6,7,8-tetrahydro-naphth-1-yl-oxy)-pyrrolidin. The compounds have a selective effect on 5-HT2C receptors in the central nervous system.
In U.S. Pat. No. 4,452,809 (filed Apr. 22, 1983) 3-aryloxy-4-hydroxypyrrolidines were disclosed, wherein it was found that 3-naphthyl or 3-indenyloxy-4-hydroxypyrrolidines have antiarrhythmic activity, whereas 3-phenoxy-4-hydroxypyrrolidines were found to have antidepressant activity. Some years earlier, in DT 2,738,477 [priority date Sep. 1, 1977] also 3-aryloxy-4-hydroxypyrrolidines were disclosed, wherein the preferred compounds with antidepressant activity were also 3-phenoxy derivatives. Other 3-aryloxypyrrolidines wherein the pyrrolidine-group of all compounds is N-substituted, having an effect on the serotonin receptor, were disclosed in EP 0,338,331 [priority date Apr. 19, 1988].
Surprisingly, after many years of research, it has now been found, that the compounds of formula I, (bicyclic aryl)oxy-substituted pyrrolidines and (bicyclic aryl)oxy-substituted azetidines wherein the 5- or 4-membered heterocycle is not substituted at any position in the ring, have a selective effect on 5-HT2C receptors in the central nervous system. Also the compounds 3-(naphth-1-yl-oxy)-pyrrolidin and 3-(5,6,7,8-tetrahydro-naphth-1-yl-oxy)-pyrrolidin, known as intermediates but not claimed in EP 0,338,331, were found to have this effect. Therefore, also protection is sought for the use of these compounds and for pharmaceutical compositions comprising them. Thus, the invention also pertains to the first medical use of the compounds according to formula 1, i.e. including the compounds 3-(naphth-1-yl-oxy)-pyrrolidin, 3-(5,6,7,8-tetrahydro-naphth-1-yl-oxy)-pyrrolidin for use as a medicament (or, in other words, for use in therapy).
The use of a selective 5-HT2C agonist ensures that pharmacological activity occurs immediately and preferentially at the 5-HT2C receptors allowing a much quicker onset of selective pharmacological activation than can be observed with SRI""s. Moreover the selectivity of the compound reduces the potential for adverse effects mediated by other serotonin receptors e.g. nausea, headache, effects which may hinder compliance and thus interfere with efficacy.
The compounds of the present invention act on the central nervous system, in particular as antidepressants, and against obsessive compulsive disorders, anxiety disorders including generalised anxiety, panic attacks, agoraphobia, eating disorders such as obesity, urinary incontinence, impotence, aggression and drug abuse such as alcohol or narcotic addiction.
Preferred compounds according to the invention have the formula I wherein the heteroatom in A, if present, is N or S; R1 is H, (1-6C) alkyl, (1-6C) alkoxy, (1-6C) alkoxy-(1-6C) alkyl; R2 is H, (1-6C) alkoxy, carbo(1-6C) alkoxy or halogen and R3 is H, (1-6C) alkyl, (1-6C) alkoxy or halogen.
More preferred are compounds of the formula (Ia) 
wherein A is an unsubstituted saturated 5-membered or optionally aromatic 6-membered ring, which may comprise a nitrogen atom adjacent to the position indicated with an asterisk; R1 is H or (1-6C) alkoxy; R2 is H, (1-6C) alkoxy or halogen; R3 is H or halogen; and n is 1 or 2. More preferred are the compounds of formula (Ia) wherein A is an unsubstituted saturated 5-membered or optionally aromatic 6-membered ring; R1 is (1-6C) alkoxy and R2 and R3 are H. Most preferrably, A in formula (Ia) is a 5-membered ring and R1 is methoxy, in particular when n is 2.
The term (1-6C) alkyl means a branched or unbranched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, t-butyl, isopentyl, and the like. The most preferred alkyl group is methyl.
The term (1-6C) alkoxy means an alkoxy group having 1-6 carbon atoms, the alkyl moiety of which having the meaning as previously defined. The most preferred alkoxy group is methoxy.
The term halogen means fluorine, chlorine or bromine.
The compounds according to formula I may be prepared in a manner conventional for such compounds. To that end, compounds of general formula II, wherein A, R1, R2, R3, X and n are as previously defined and P is any N-protecting group, stable under alkaline conditions [suitable N-protecting groups can be found in T. W. Green and P. G. M. Wuts: Protective Groups in Organic Synthesis, Second Edition (Wiley, N.Y., 1991)], are deprotected using the appropriate conditions such as catalytic hydrogenation or intermediate carbamate formation, followed by reaction with alcohols. Optionally at the same time, a salt may be formed. 
The compounds according to general formula II may be prepared by arylether formation of suitable N-protected 3-hydroxy-azetidines or -pyrrolidines, wherein the protecting group is as hereinbefore defined, with appropriately substituted aromatic or heteroaromatic compounds bearing a suitable leaving group. Alternatively, N-protected-azetidines or -pyrrolidines bearing a suitable leaving group at the 3-position, such as halogen, triflate, tosylate or mesylate, can be reacted with appropriately substituted aromatic or heteroaromatic compounds bearing a hydroxy, or mercapto group.
The compounds of the invention, which can be in the form of a free base, may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts may also be obtained by treating the free base of formula I with an organic or inorganic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.
The compounds of this invention may possess one or more chiral carbon atoms, and may therefore be obtained as a pure enantiomer, or as a mixture of enantiomers, or as a mixture containing diastereomers. Methods for obtaining the pure enantiomers are well known in the art, e.g. crystallization of salts which are obtained from optically active acids and the racemic mixture, or chromatography using chiral columns.
The compounds of the invention may be administered enterally or parenterally, and for humans preferably in a daily dosage of 0.001-100 mg per kg body weight, preferably 0.01-10 mg per kg body weight. Mixed with pharmaceutically suitable auxiliaries, e.g. as described in the standard reference, Gennaro et at., Remington""s Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture) the compounds may be compressed into solid dosage units, such as pins, tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable liquids the compounds can also be applied in the form of a solution, suspension, emulsion, e.g. for use as an injection preparation, or as a spray, e.g. for use as a nasal spray. For making dosage units, e.g. tablets, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used.
Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.